The 2019 NIH ME/CFS conference was punctuated by a provocative question from the audience. Raise your hand if you’ve heard of alpha-gal allergy. The room was motionless. My interest was piqued. Since tick-borne illness mimics chronic illnesses like ME/CFS and fibromyalgia, how come these physicians are unaware of this condition?

The Red Meat Allergy

First discovered in 2007, some individuals bitten by ticks later acquire an apparent allergy to red meat. At first, it seemed almost too wild to believe. And yet, tick bites and subsequent allergy to animal foods have now been reported from multiple countries, including Australia, Sweden, France, Spain, Japan, and the United States. The southeastern United States is the most susceptible region. But many reports show that cases are spreading, in Long Island, Minnesota, Maine, and New Hampshire.

The alpha-gal allergy is triggered by an IgE antibody response when exposed to the carbohydrate galactose-alpha-1,3-galactose (alpha-gal). This carbohydrate is present in tick saliva and thus transmitted upon bite. However, it is also found in animal meats, gelatin, and some drugs. For instance, the monoclonal antibody drug Cetuximab has a structure abundant with alpha-gal. Some patients administered the drug experience severe, sometimes fatal, anaphylaxis as their immune systems produce excessive antibodies to the drug.

*Of note, the now shelved ME/CFS trial drug Rituximab, which is the same drug class as Cetuximab, does not have an alpha-gal structure.

Which Ticks?

Not all ticks carry alpha-gal in their saliva. The main culprit is amblyomma americanum, also known as the Lone Star tick due to the white Texas-shaped spot on its back. But in Europe, Ixodes ricinus, or the castor bean tick, also is able to trigger the immune response to alpha-gal. In Australia, the hard tick, (Ixodes (Endopalpiger australiensis) and the Australian paralysis tick (Ixodes holocyclus), are also implicated. In time, we will discover more tick species in different geographical areas associated with alpha-gal allergy.

Alpha-Gal Syndrome

Tick bites induce high levels of anti-alpha-gal IgE antibodies in humans—a 20x increase in antibody production! Unlike most allergic reactions, patients do not develop food allergy symptoms for up to 5 hours after eating meat. Alternately, symptoms may not develop for 6 months following the initial bite. With this long delay, it is difficult for the individual and the physician to connect the dots about this strange condition. This may also unfortunately prompt the diagnosing doctor to miss the connection and presume a psychosomatic condition or ME/CFS-like condition. However, the symptoms are distinctly different than either of these conditions with little overlap with ME/CFS.

The tick bite may initially cause inflammation around the bite site or, less commonly, mild to severe anaphylaxis immediately. In others, symptoms may be less pronounced and delayed. They include nausea, diarrhea, stomach pain or indigestion, mild blood vessel swelling, and itchy rashes. These symptoms may mimic mast cell activation syndrome/histamine intolerance or a typical food allergy.

How to Test for Alpha-Gal Syndrome

A skin prick tests for cooked meats using the prick-to-prick method are used but not very sensitive. Skin prick and intradermal tests with cetuximab are an option and give better results but are high cost. More reliable testing is available with skin prick of raw meats or sIgA assays.

Alpha-Gal, Why Now? 

Alpha-gal allergy is not a new phenomenon. Most mammals have the carbohydrate in their skeletal muscles—mammals other than primates. The hypersensitive immune reaction to alpha-gal is one explanation why donor tissue and organ transplant from non-primate animals is difficult to achieve in humans. The connection to ticks and alpha-gal is recent and cases of meat allergy continue to rise. Why is this happening now when people have eaten animal meat for millennia?

Other tick-borne illnesses on the rise point to climate change as a major factor in transmission to humans. More ticks, more bites, more exposure to alpha-gal. However, another explanation may be changes in the microbiome of ticks AND humans. Alpha-gal is continuously produced by bacteria of the normal flora. The alpha-gal sugar contained in the saliva of ticks is likely produced from bacteria that inhabit the ticks. This could result in far higher concentrations of the sugar in the saliva than previous times, resulting in a high likelihood of allergy in those bitten.

Alpha-Gal in the Human Gut

In humans, changes in our microbiomes may make us more susceptible to alpha-gal hypersensitivity. Perhaps we have fewer and fewer microbiota that produce alpha-gal to sensitize us to it over time. Then when exposed to high concentrations of tick spit with alpha-gal, our immune systems react over zealously. Perhaps we were once sensitized to alpha-gal and our immune systems are losing their ability to tolerate exposure to the sugar thanks to overuse of antibiotics and other factors that alter the biome.

Keep in mind that not all meats contain the same degree of alpha-gal. The fattier cuts seem to allow for more alpha-gal to be absorbed into the bloodstream, thus triggering a stronger immune reaction than leaner meats. Some have also suggested that alcohol consumed with meats can augment the allergic reaction because the intestinal lining is more permeable to alpha-gal. One can surmise that any drug or food that increases intestinal permeability can lead to increased alpha-gal absorption and stronger immune reactions.

As we understand this further, the future may provide vaccines or even probiotics to combat the allergy by re-educating the immune system to a time when meat allergy was nonexistent.

The Bottom Line

Tick bites can induce meat allergy in humans through transmission of the sugar alpha-gal. Tick avoidance is key to prevent this immune reaction. The microbiome produces alpha-gal and our bodies generate antibodies throughout life. The antibodies produced after alpha-gal exposure via tick saliva are more allergenic than ever before in history. Microbiome changes in humans or ticks may be contributing to this rise in allergy, as there is less immune sensing to alpha-gal. Those who develop the allergy must avoid red meats and foods that contain products sourced from animal meats, such as gelatin.

References

Commins SP & Platts-Mills TA. (2013) Tick bites and red meat allergy. Curr Opin Allergy Clin Immunol. 13(4):354-9.

de la Fuente J et al. (2019) The alpha-Gal syndrome: new insights into the tick-host conflict and cooperation. Parasit Vectors. 12(1):154.

Steinke JW, Platts-Mills TA & Commins SP. (2015) The alpha-gal story: lessons learned from connecting the dots. J Allergy Clin Immunol. 135(3):589-96

Bircher AJ et al. (2017) Food allergy to the carbohydrate galactose-alpha-1,3-galactose (alpha-gal): four case reports and a review. Eur J Dermatol. 27(1):3-9.